Mixtures of Heteropolycycles

ABSTRACT

A mixture of heteropolycycles has preferably two particular heteropolycycles and more preferably, no more than 10 wt. %, 5 wt. %, 2.5 wt. %, 1 wt. %, 0.5 wt. %, 0.1 wt. %, 0.01 wt. %, 0.001 wt. %, or no more than a detectable amount of one of the two.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuing application based on PCT/US2015/053066,filed Sep. 30, 2015, and claims priority to U.S. provisional applicationSer. No. 62/057,939, filed Sep. 30, 2014, each of which is incorporatedby reference in its entirety herein.

FIELD OF THE INVENTION

The invention relates to heteropolycyclic, particularly diaza- andoxaza-polycyclic, organic compounds.

BACKGROUND OF THE INVENTION

Piperazine and morpholine-like compounds are relevant in the chemicalindustry, particularly the pharmaceutical industry, and are buildingblocks or components for a number of pharmacologically activesubstances, particularly in enhancing the bioavailability and/orantagonistic adhesion of pharmaceuticals.

Piperazine itself can be produced as one of the products in the reactionof 1,2-dichloroethane or ethanolamine with ammonia, whereby piperazineis separated from the product streams, possibly containingethylenediamine, diethylenetriamine, and other related linear and cyclicanalogs. Piperazine is consequently inexpensive relative to its bridgedanalogs. Likewise, morpholine may be produced by the dehydration ofdiethanolamine with sulfuric acid, and is similarly inexpensive due tothe scalability of its industrial synthesis.

Bridged analogs of morpholine and piperazine are very interestingalternatives to their unbridged analogs, particularly for their ease ofexchange with piperazine and/or morpholine, and because such bridgedspecies, due to their restrained degrees of freedom and translation, mayprovide more efficiently binding products upon such substitution of thenon-bridged analog for the bridged. However, most known routes to thesebridged analogs of piperazine, morpholine, and other heteropolycyclesare not commercially viable due to the high costs from any of extensivesynthetic steps, complicated and numerous separations, and high materialand equipment outlays of the known alternative processes.

Numerous academic and industrial research groups have pursued new orimproved methods for synthesizing such compounds, particularly methodswhich are scalable. Amongst a number of useful and relevant bridgedanalogs of piperazine are 3,8-diazabicyclo[3.2.1]octanes,2,5-diazabicyclo[2.2.1]heptanes, 3,6-diazabicyclo[3.1.0]hexanes,

3,6-diazabicyclo[3.1.1]heptane, and 2,5-diazabicyclo[2.2.2]octanes,

Based on the numerous known syntheses discussed in the literature,summarized in U.S. Appl. Ser. No. 62/057,939, it is clear that there isa need for alternate synthetic approaches to heteropolycycles, which mayemploy cheaper starting materials and/or reduce the overall steps to theend product.

A legalistic search into whether and how the scope of the inventionsreported herein could be affected by publications imputed byinternational patent laws to be known to those of ordinary skill in theart (although such publications were not known to the inventors, norimpacted the formative thinking of the invention), revealed certainpublications which warrant pre-emptive discussion.

One publication discloses the reaction of a 1:2,5:6-bisepoxyoctadienewith methylamine to form a heteromonocycle, which is subsequentlyacetylated with acetic anhydride. Michel, P.; Rassat, A. An Easy Accessto 2,6-Dihydroxy-9-azabicyclo[3.3.1]nonane, a Versatile Synthon. J. Org.Chem. 2000, 65, 2572-2573. Michel produces only a polycycle having asingle heteroatom, nitrogen, integrated into the polycyclic backbone(skeleton), and is silent on modifying the products to have even twoheteroatoms in the ring backbone, instead seeking to produce, interalia, nitroxide biradicals. Another reference of this type discloses theformation of heteropolycycle by the reaction of a1:2,5:6-bisepoxyoctadiene with an alkylamine, but fails to disclose orsuggest the formation of a heteropolycycle having more than oneheteroatom, instead limiting its disclosure to the complicatedenantiomers and spectroscopic properties of the9-azabicyclo[3.3.1]nonanes. Bieliunas, V.; Rackauskaite, D.; Orentas,E.; Stoncius, S. Synthesis, Entiomer Separation, and AbsoluteConfiguration of 2,6-Oxygenated 9-Azabicyclo[3.3.1]nonanes. J. Org.Chem. 2013, 78, 5339-5348.

Another publication discloses the reaction of a derivative of adi-epoxidized amide form of diallylamine, as a small portion of muchmore complicated liposidomycin-analogs at pg. 3930 (29a:29b to 30a:30bin Scheme 4). Sarabia, F.; Martin-Ortiz, L.; Lopez-Herrera, F. J. AConvergent Synthetic Approach to the Nucleoside-Type LiposidomycinAntibiotics. Org. Lett. 2003, 5(21), 3927-3930. Not only does Sarabianot produce a polycycle, but rather only a monoheterocycle, the reactionin question would not have lent itself to further cyclization within thescope of this invention, even if such a reaction were suggested andwould have been reasonably expected to function.

A further reference discloses separate reactions of a derivative of1:2,4:5-bisepoxypentane with an alkylamine to give variousdihydroxypiperidines. Concellon; J. M.; Rivero, I. A.; Rodriguez-Solla,H.; Concellon. C.; Espana, E.; Garcia-Granda, S.; Diaz, M. R. TotallySelective Synthesis of Enantiopure(3S,5R)-4-Amino-3,5-dihydroxypiperidines from Aminodiepoxides Derivedfrom Serine. J. Org. Chem. 2008, 73(15), 6048-6051. Concellon, however,does not suggest further cyclization, nor that a target product shouldinclude two or more heteroatoms in the backbone of any suchheteropolycycle.

A further reference discloses a reaction of two epoxides in the ultimateformation of a heteropolycycle with two or more heteroatoms in the ringbackbone. Breuning, M.; Steiner, M.; Mehler, C.; Paasche, A.; Hein, D. AFlexible Route to Chiral 2-endo-Substituted 9-Oxabispidines and TheirApplication in the Enantioselective Oxidation of Secondary Alcohols. J.Org. Chem. 2009, 74(3), 1407-1410. However, Breuning does not disclosereacting a bisepoxide, nor a single-pot reaction of two epoxides upon asingle starting molecule.

Similarly, WO 2006/137769 A1 discloses the reaction of a bisepoxidatedanalog of diallyl amine, and ultimately forms a heteropolycycle from theheteromonocyclic diol intermediate. However, WO 2006/137769 A1 disclosesonly oxadiazabispidine analogs which have nitrogen heteroatomsintroduced into to heteropolycyclic backbone without the use of an(amine) nucleophile, i.e., with a sulfonamide and epichlorohydrin, basedon the particular reaction sequence suggested therein, e.g., at pg. 18.Bisepoxides lacking hydroxyl substituents are not disclosed or suggestedby WO 2006/137769 A1, nor is the production of a heteropolycycle intowhich each nitrogen is introduced by an amine nucleophile. WO2013/050938 A1 also discloses subject matter related to the reaction ofan N-protected epoxidized analog of diallylamine, producingoxadiazabispidine analogs, i.e., heteropolycycles. However, WO2013/050938 A1 likewise describes the reaction of a protected startingmaterial, already having a nitrogen in the backbone chain. Unlike theclaimed embodiments of the present invention, which introduce all of thenitrogen heteroatoms into the skeleton of the claim, WO 2013/050938 A1discloses already introducing a nitrogen into the heteropolycycle beforethe reaction of the bisepoxide, see, e.g., pg. 47-48. Moreover, WO2013/050938 A1 does not disclose or suggest a reaction which introducesall heteroatoms, or at least all nitrogen heteroatoms, into thepolycyclic backbone after reacting the bisepoxide. US 2009/0326221 A1and US 2010/0160626 A1 suffer from the same fundamental flaws. Moreover,WO 2006/137769 A1 and its kin disclose only oxygenated analogs ofbispidine, and do not suggest larger or smaller rings, nor rings having2, 4, or more heteroatoms in the heteropolycyclic backbone.

Another set of references discloses the reaction of certain sugarbisepoxides with alkylamines to obtain polyhydroxylated azepanes. Orwig,S. D.; Tan, Y. L.; Grimster, N. P.; Yu, Z.; Powers, E. T.; Kelly, J. W.;Lieberman, R. L. Binding of 3,4,5,6-Tetrahydroxyazepanes to theAcid-β-glucosidase Active Site: Implications for PharmacologicalChaperone Design for Gaucher Disease. Biochemistry 2011, 50,10647-10657; WO 95/022526 A1. However, none of these iditol referencesprovides a motivation to create a polycyclic compound from the obtainedazepanes, nor any indication that such further processing would beachievable. U.S. Pat. No. 6,462,193 BI is of similar deficient characterin this regard.

A further publication discloses a reaction of a bisepoxide with anucleophile. Paul, R.; Tehelitcheff. S. Diethylenic hydrocarbons: II.Synthesis of 3,5-dihydroxy-1-substituted piperidines from1,4-pentadiene. Bull. Soc. Chim. France 1948, 10, 896-900. Paul,however, only produces a heteromonocycle, and makes no mention ofpolycyclic compounds. Furthermore, were the piperidine monocyclessuggestive of polycycles, more than a half century has passed sincePaul's publication, a substantially long period of time.

A 2014 reference discloses a method of producing3,8-diazabicyclo[3.2.1]octane by an oxidative route from 1,5-hexadiene,but its method does not employ epoxidation and requires asulfonamide-protected amine for the initial ring opening step. Shainyan,B. A.; Moskalik, M. Y.; Astakhova, V. V.; Schilde, U. Novel design of3,8-diazabicyclo[3.2.1]octane framework in oxidative sulfonamidation of1,5-hexadiene. Tetrahedron 2014, 70, 4547-4551.

A further 2014 reference discloses a reaction of a bis-epoxide with anamine nucleophile to form a cyclic species, but the post-epoxidationreaction sequence disclosed therein does not further cyclize the productof the epoxide opening and furthermore forms a heteropolycycle havingonly a single heteroatom in its carbon backbone. Grenning, A. J.;Snyder, J. K.; Porco, Jr., J. A. Org. Lett. 2014, 16, 792-795.

BRIEF SUMMARY OF THE INVENTION

An aspect of the invention provides a method of synthesizing aheteropolycycle, the method comprising: reacting a bisepoxide with afirst heteroatom nucleophile, to obtain a mixture comprising a diolcompound; and further processing, to obtain the heteropolycyclecomprising at least two heteroatoms within its polycyclic backbone,wherein each nitrogen within the polycyclic backbone of theheteropolycycle is preferably introduced into the polycyclic backbonevia an amine nucleophile. An aspect of the invention is the synthesis ofa heteropolycycle without employing a reduction, particularly withoutreducing a carbonyl, and preferably employing a bisepoxide but withoutemploying an optionally N-protected bisepoxidized diallyl amine.

DETAILED DESCRIPTION OF THE INVENTION

Methods within the scope of the invention generally involve reacting abisepoxide with a nucleophile to give an intermediate, whereby theintermediate can be optionally protected, optionally activating alcoholsof the resulting intermediates with leaving groups, and again cyclizedto give a heteropolycycle, wherein preferably all nitrogens, morepreferably all N, O, S, and/or P heteroatoms, most preferably allheteroatoms, in the heteropolycyclic backbone are introduced vianucleophiles which are distinct molecules from the bisepoxide,preferably as the reactive nucleophilic element of the nucleophile(s).An aspect of the invention involves forming a heteropolycycle from anon-cyclic starting material or from a compound containing nonon-epoxide cyclic moieties, without a reduction, particularly without areduction of a carbonyl. The inventive process preferably avoids the useof epichlorohydrin, preferably avoids the use of a sulfonamidenucleophile.

An aspect of the invention provides a method of synthesizing apharmaceutical compound, the method comprising: reacting, with a firstheteroatom nucleophile, a bisepoxide of formula (I) or (II)

wherein a hyphenated line indicates that the bond is optionally absent,-A- is a bond, hydrogen, (CH₂)_(m)C, C(CH₂)_(m), (CH₂)_(m)C(CH₂)_(n),CH(CH₂)_(m), (CH₂)_(m)CH, (CH₂)_(m)CH(CH₂)_(n), (CH₂)_(m)CH₃,CH₂(CH₂)_(m)OH, CH₂(CH₂)_(m)OR, CH₂(CH₂)_(m)SH, CH₂(CH₂)_(m)SR,CH₂(CH₂)_(m)NH₂, CH₂(CH₂)_(m)NHR, CH₂(CH₂)_(m)NR₂, CH₂(CH₂)_(m)PH₂,CH₂(CH₂)_(m)PHR, or CH₂(CH₂)_(m)PR₂, -B- is a bond, hydrogen,(CH₂)_(o)C, C(CH₂)_(o), (CH₂)_(o)C(CH₂)_(p), CH(CH₂)_(o), (CH₂)_(o)CH,(CH₂)_(o)CH(CHo₂)_(p), (CH₂)_(o)CH₃, CH₂(CH₂)_(o)OH, CH₂(CH₂)_(o)OR,CH₂(CH₂)_(o)SH, CH₂(CH₂)_(o)SR, CH₂(CH₂)_(o)NH₂, CH₂(CH₂)_(o)NHR,CH₂(CH₂)_(o)NR₂, CH₂(CH₂)_(o)PH₂, CH₂(CH₂)_(o)PHR, or CH₂(CH₂)_(o)PR₂,-C- is a bond, (CH₂)_(q), (CH₂)_(q)C, C(CH₂)_(q), (CH₂)_(q)C(CH₂)_(r),CH(CH₂)_(q), (CH₂)_(q)CH, or (CH₂)_(q)CH(CH₂)_(r), -D- is a bond,(CH₂)_(s), (CH₂)_(s)C, C(CH₂)_(s), (CH₂)_(s)C(CH₂)_(t), CH(CH₂)_(s),(CH₂)_(s)CH, or (CH₂)_(s)CH(CH₂)_(t), -E- is absent or a bond,(CH₂)_(u), (CH₂)C, C(CH₂)_(u), (CH₂)_(u)C(CH₂)_(v), CH(CH₂)_(u),(CH₂)_(u)CH, (CH₂)_(u)CH(CH₂)_(v), or (CH₂)_(u)CH₃, -F- is absent or abond, hydrogen, (CH₂)_(h)C, C(CH₂)_(h), (CH₂)_(h)C(CH₂)_(j),CH(CH₂)_(h), (CH₂)_(h)CH, (CH₂)_(h)CH(CH₂)_(j), (CH₂)_(h)CH₃,CH₂(CH₂)_(h)OH, CH₂(CH₂)_(h)OR, CH₂(CH₂)_(h)SH, CH₂(CH₂)_(h)SR,CH₂(CH₂)_(h)NH₂, CH₂(CH₂)_(h)NHR, CH₂(CH₂)_(h)NR₂, CH₂(CH₂)_(h)PH₂,CH₂(CH₂)_(h)PHR, or CH₂(CH₂)_(h)PR₂, -G- is absent or a bond, hydrogen,(CH₂)_(k)C, C(CH₂)_(k), (CH₂)_(k)C(CH₂)_(l), CH(CH₂)_(k), (CH₂)_(k)CH,(CH₂)_(k)CH(CH₂)_(l), (CH₂)_(k)CH₃, CH₂(CH₂)_(k)OH, CH₂(CH₂)_(k)OR,CH₂(CH₂)_(k)SH, CH₂(CH₂)_(k)SR, CH₂(CH₂)_(k)NH₂, CH₂(CH₂)_(k)NHR,CH₂(CH₂)_(k)NR₂, CH₂(CH₂)_(k)PH₂, CH₂(CH₂)_(k)PHR, or CH₂(CH₂)_(k)PR₂,h, j, k, l, m, n, o, p, q, r, s, t, u, and v are independently 0, 1, 2,or 3, -X- is absent or is NH, O, S, or PH, and -Y- is a bond, O, S, orPH, each R is independently hydrogen or an optionally substitutedmethyl, ethyl, C₃ alkyl group, C₄ alkyl group, C₅ alkyl group, C₂alkenyl group, C₃ alkenyl group, C₄ alkenyl group, C₅ alkenyl group,formyl, carboxylate, hydroxymethyl, acetyl, isovaleryl, or optionallysubstituted phenyl, wherein 1, 2, 3, or 4 hydrogens upon any alkyl groupof -A-, -B-, -C-, -D-, -E-, or R (meaning, herein, that one or morehydrogens from any of -A- through R, or only one of -A-through R, and/orwhen R is H, optionally replacing R) is optionally replaced by an azide,amine, nitrile, isonitrile, isocyanate, thiocyanate, isothiocyanate,nitro, nitroso, thiol, thioether, fluoride, chloride, bromide, oriodide, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl,iso-butyl, sec-butyl, vinyl, C₃ alkenyl group, C₄ alkenyl group, C₅alkenyl group, OCH₃, OCH₂CH₃, OCH₂CH₂CH₃, OCH(CH₃)₂, OCH₂CH₂CH₂CH₃,isobutoxy, sec-butoxy, methoxymethyl, methoxyethyl, ethoxymethyl,(hetero)aryl ether (meaning heteroaryl or aryl), C₁-C₅ carboxylate,C₀-C₅ sulfonate, C₁-C₁₀ (reverse) amide (meaning amide C(O)N or reverseamide NC(O)), C₁-C₁₀ (reverse) ester, C₁-C₁₀ (reverse) carbamate, C₀-C₁₀(reverse) sulfonamide, C₀-C₁₀ (reverse) sulfonic ester, C₁-C₆ ketal,C₁-C₅ ketone, or C₁-C₅ aldehyde, wherein 2 to 4 hydrogens upon any alkylgroup of -A-, -B-, -C-, -D-, -E-, or R are optionally removed to form anoptionally substituted C₃-C₁₀ ring, wherein two hydrogens upon any alkylgroup of -A-, -B-, -C-, -D-, -E-, or R are optionally removed to form acarbonyl, ketal, or an exo-C₁-C₄ alkenyl group, to obtain a mixturecomprising a diol compound; and further processing, to obtain theheteropolycycle comprising at least two heteroatoms within itspolycyclic backbone.

An aspect of the invention provides a method of synthesizing apharmaceutical compound, the method comprising: reacting a bisepoxide asdescribed herein with a heteroatom nucleophile, to obtain a mixturecomprising a diol compound; further processing, to obtain theheteropolycycle; and reacting the heteropolycycle with a precursorcomponent to the pharmaceutical compound, and, optionally, furthertreating a product of the reacting, to obtain the pharmaceuticalcompound. Preferably the method of synthesizing the pharmaceuticalcompound or the heteropolycycle is one wherein the further treatingcomprises functionalizing, e.g., acylating or alkylating, a nitrogen ofthe product of the reacting, and/or forming a pharmaceutically suitablesalt of the product of reacting.

An aspect of the invention is the method of synthesizing aheteropolycycle, the method comprising: reacting a bisepoxide of formula(II):

wherein -A- may be absent (i.e., 1:2,3:4-diepoxybutane analogs), oroptionally substituted methylene, ethylene, propylene, CH₂OCH₂, CH₂SCH₂,CH₂N(R)CH₂, (R here preferably not forming a sulfonamide), CH₂P(R)CH₂,CH₂OCH₂CH₂, CH₂SCH₂CH₂, CH₂N(R)CH₂CH₂, CH₂P(R)CH₂CH₂, CH₂CH₂OCH₂CH₂,CH₂CH₂SCH₂CH₂, CH₂CH₂N(R)CH₂CH₂, CH₂CH₂P(R)CH₂CH₂, CH₂OCH₂CH₂CH₂,CH₂SCH₂CH₂CH₂, CH₂N(R)CH₂CH₂CH₂, CH₂P(R)CH₂CH₂CH₂, CH₂CH₂OCH₂CH₂CH₂,CH₂CH₂SCH₂CH₂CH₂, CH₂CH₂N(R)CH₂CH₂CH₂, CH₂CH₂P(R)CH₂CH₂CH₂, wherein 1,2, 3, 4, or 5 protons of any of the foregoing may be replaced by asubstituent, two hydrogens upon any alkyl group of -A- and/or Roptionally being removed to form an optionally substituted C₃-C₇(hetero)cyclic ring, and R is independently, hydrogen, azide, amine,nitrile, isonitrile, cyanate, isocyanate, thiocyanate, isothiocyanate,nitro, nitroso, thiol, thioether, fluoride, chloride, bromide, iodide,methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl,methoxy (OCH₃), ethoxy (OCH₂CH₃), propoxy (OCH₂CH₂CH₃), isopropoxy(OCH(CH₃)₂), butoxy (OCH₂CH₂CH₂CH₃), isobutoxy, sec-butoxy, cyano,methoxymethyl, methoxyethyl, ethoxymethyl, hydroxy, C₁-C₄ carboxylate(reverse), C₀-C₄ sulfonate, C₁-C₄ (reverse) amide, C₁-C₄ (reverse)ester, C₁-C₄ (reverse) carbamate, C₁-C₄ (reverse) sulfonamide, C₁-C₄ketone, or C₁-C₄ aldehyde, with a nucleophile; and further processing,to obtain the heteropolycycle. In this application, “reverse” in thecontext of, e.g., carbonyl compounds, means —CH₂OC(O)CH₂—, rather than—CH₂C(O)OCH₂—.

A preferred embodiment of the invention produces a heteropolycyclecomprising 2,5-diazabicyclo[2.2.2]octane(s), in some circumstances, both2,5-diazabicyclo[2.2.2]octane(s) and 3,8-diazabicyclo[3.2.1]octane(s).This approach may, in some embodiments, preferably produce primarily,i.e., 75%, 85%, 90%, 95%, 99%, or only a 2,5-diazabicyclo[2.2.2]octane.Alternatively, this approach may, in some embodiments, preferablyproduce primarily, i.e., 75%, 85%, 90%, 95%, 99%, or only a3,8-diazabicyclo[3.2.1]octane. A further embodiment in this approach mayproduce anywhere in the ranges 1:1, 1:2, 2:3, 1:3, 3:2, 3:1, 1:4, and/or4:1 of a mixture of products, 2,5-diazabicyclo[2.2.2]octane(s) and3,8-diazabicyclo[3.2.1]octane(s). Such an embodiment may proceed, e.g.,from 1,5-hexadiene, or the bisepoxide thereof.

A preferred embodiment of the invention produces2,5-diazabicyclo[2.2.1]heptane(s) and 3,6-diazabicyclo[3.1.1]heptane(s),more preferably, 3,6-diazabicyclo[3.1.1]heptane(s). This approach may,in some embodiments, preferably produce primarily, i.e., 75%, 85%, 90%,95%, 99%, or only a 3,6-diazabicyclo[3.1.1]heptane. Such an embodimentmay proceed, e.g., from 1,4-pentadiene, or the bisepoxide thereof.

A preferred embodiment of the invention produces3,6-diazabicyclo[3.1.0]hexane(s) and 2,5-diazabicyclo[2.2.0]hexane(s),more preferably, 3,6-diazabicyclo[3.1.0]hexane(s). This approach may, insome embodiments, preferably produce primarily, i.e., 75%, 85%, 90%,95%, 99%0, or only a 3,6-diazabicyclo[3.1.0]hexane(s). Such anembodiment may proceed, e.g., from 1,3-butadiene, or the bisepoxidethereof.

In a particularly preferred embodiment of the invention, the bisepoxidecomprises 1:2,3:4-bisepoxybutane, 1:2,4:5-bisepoxypentane,1:2,5:6-bisepoxyhexane, or 1:2,6:7-bisepoxyheptane, most preferably1:2,5:6-bisepoxyhexane. Any of these bisepoxides is preferably usedindividually, i.e., not as a mixture of homologs. Preferable embodimentsmay employ stereospecific epoxidizing methods known in the art (e.g.,Sharpless, Shi, Jacobsen-Katsuki, etc.) to use particularstereochemically enriched or pure enantiomers or diastereomers of thebisepoxide. A preferred embodiment includes producing a nonracemicheteropolycycle by, e.g., optically resolving the racemic productmixture with a nonracemic acid, through repeated recrystallization ofthe formed salts from a suitable solvent, or via asymmetric synthesis,by employing a nonracemic nucleophile, such as a naturally occurringand/or stereopure nucleophile. The purity of the bisepoxide can be anythat does not hinder facile separation. The purity of the bisepoxide ispreferably at least 90%, but may be any level of purity reaching thelimits of HPLC detection. The stereopurity of an enriched bisepoxide, orisolated heteropolycycle may be, for example, at least 60, 70, 75, 80,85, 90, 95, 96, 97, 97.5, 98, 98.5, 99, 99.5, 99.9, or 99.99 e.e., up tothe limits of detection.

The inventive method is preferably one wherein the further processingcomprises displacing the leaving group-activated hydroxyl group with asecond heteroatom-comprising nucleophile to form a raw mixturecomprising the heteropolycycle. The method may further comprisepurifying the raw mixture to obtain a purified mixture which is enrichedof the heteropolycycle relative to the raw mixture. In fact, at any stepof the reaction, the product mixtures may be purified, which mayinclude, for example, separating diastereomers from each other and/or achiral separation. The method of the invention preferably producessingle racemates. However, in certain embodiments, it could bepreferably not to separate intermediates until the final heteropolycycle(preferably, bicyclic or tricyclic, most preferably bicyclic). In suchan embodiment, the method preferably involves a further processingcomprising separating two different heteropolycycles in the raw mixturefrom each other, wherein the two different heteropolycycles respectivelyhave a different bonding arrangement of a bridging portion of eachheteropolycycle.

After the bisepoxidation, certain embodiments of the invention employ anamine or phosphine to open the epoxides and form a ring. This approachgenerally produces a diol, which may be reacted, optionally withprotection of the amine or phosphine, to generate two leaving groups outof the hydroxides. Examples of such leaving groups are tosylates,sulfates, optionally substituted phenylsulfonates, mesylates,trifluoroacetates, triflates, nosylates, chlorides, bromides, iodides,and triphenyiphosphineoxides. Inventive embodiments comprisingactivating at least one hydroxyl group of the diol compound with aleaving group forming compound, thereby converting the hydroxyl groupinto a better leaving group relative to the hydroxyl group, andobtaining an intermediate comprising a leaving group-activated hydroxylgroup, may involve contacting at least two, only two, at least three,only three, etc., hydroxyl groups of the diol compound with the leavinggroup forming compound, to obtain the intermediate comprising twoleaving-group activated hydroxyl groups.

A bicyclizable diastereomer of 5(S)-hydroxy-2(R)-piperidinemethanol andits enantiomer are seen in Scheme 11 of U.S. 62/057,939. Thediastereomeric outcome of the epoxide opening, in embodiments in whichno stereopure bisepoxide is used, or a bisepoxide is used wherein thedesired diastereomers are present in the form of a racemate of desiredenantiomers, may provide 2R,5R and 2S,5S enantiomers and thediastereomeric meso compound in the case of 1:2,5:6-bisepoxyhexane. The2R,5R and 2S,5S enantiomers cannot bicyclize in a reaction proceedingunder S_(N)2 conditions. Only the meso compound bicyclizes under S_(N)2conditions.

Suitable starting materials for the bisepoxide include essentially anydiene, such as butadiene, 1,4-pentadiene, 1,3-pentadiene, 1,5-hexadiene,1,4-hexadiene, 1,3-hexadiene, 2,4-hexadiene, 1,6-heptadiene,1,5-heptadiene, 1,4-heptadiene, 2,5-heptadiene, 3,5-heptadiene,1,7-octadiene, 1,6-octadiene, 2,6-octadiene, 2,5-octadiene,1,5-octadiene, 2,4-octadiene, cyclopentadiene, 1,3-cyclohexadiene,1,4-cyclohexadiene, 1,4-oxazine, 1,4-dioxin, norbornadiene,dicyclopentadiene, 4-vinylcyclohexene, 3-vinylcyclohexene,1-vinylcyclohexene, i.e., any vinylcyclohexene, hepta-2,6-dienoic acid,1,2-divinylbenzene or other substituted arene or heteroarene carryingtwo or more unsaturations in sidechains on adjacent positions of thearyl core, i.e., ortho to one another (e.g., benzene, naphthalene,pyridine, pyrazine, purine, indolizine, quinolizine, pyridazine,imidazole, indole, isoindole, naphthyridine, quinoline, isoquinoline,pyrrole, furan, thiophene, phosphole, borole, arsole, stibole, silole,bismole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, oxazines,carbazole and other benzo-fused and/or partially hydrogenated analogs ofthese, etc.), a saturated cyclic compound having approx. 2-5carbon-carbon bond distance (for example, 1-4 atomic) spaced alkenylsubstituents (e.g., 1,1-divinylcyclopropane, 1,2-divinylcyclopropane,1,1-divinylcyclobutane, 1,2-divinylcyclobutane, 1,3-divinylcyclobutane,1,1-divinylcyclopentane, 1,2-divinylcyclopentane,1,3-divinylcyclopentane, 1,1-divinylcyclohexane, 1,2-divinylcyclohexane,1,3-divinylcyclohexane, 1,4-divinylcyclohexane, 1,1-divinylcycloheptane,1,2-divinylcycloheptane, 1,3-divinylcycloheptane,1,4-divinylcycloheptane, 1,2-divinylaziridine, 2,2-divinylaziridine,2,3-divinylaziridine, 2,2-divinyloxirane, 2,3-divinyloxirane,2,2-divinylthiirane, 2,3-divinylthiirane, 2,2-divinyloxetane,2,3-divinyloxetane, 3,3-divinyloxetane, 2,4-divinyloxetane,1,2-divinylazetidine, 2,2-divinylazetidine, 1,3-divinylazetidine,2,3-divinylazetidine, 3,3-divinylazetidine, 2,4-divinylazetidine,2,2-divinylthietane, 2,3-divinylthietane, 3,3-divinylthietane,2,4-divinylthietane, 1,2-divinylpyrrolidine, 2,2-divinylpyrrolidine,1,3-divinylpyrrolidine, 2,3-divinylpyrrolidine, 3,3-divinylpyrrolidine,2,4-divinylpyrrolidine, 3,4-divinylpyrrolidine, 2,5-divinylpyrrolidine,2,2-divinyltetrahydrofuran, 2,3-divinyltetrahydrofuran,3,3-divinyltetrahydrofuran, 2,4-divinyltetrahydrofuran,3,4-divinyltetrahydrofuran, 2,5-divinyltetrahydrofuran,2,2-divinylphospholane, 2,3-divinylphospholane, 3,3-divinylphospholane,2,4-divinylphospholane, 3,4-divinylphospholane, 2,5-divinylphospholane,2,2-divinylthiolane, 2,3-divinylthiolane, 3,3-divinylthiolane,2,4-divinylthiolane, 3,4-divinylthiolane, 2,5-divinylthiolane,1,2-divinylpiperidine, 2,2-divinylpiperidine, 1,3-divinylpiperidine,2,3-divinylpiperidine, 3,3-divinylpiperidine, 1,4-divinylpiperidine,2,4-divinylpiperidine, 3,4-divinylpiperidine, 4,4-divinylpiperidine,2,5-divinylpiperidine, 3,5-divinylpiperidine, 2,6-divinylpiperidine,1,2-divinylpiperazine, 2,2-divinylpiperazine, 1,3-divinylpiperazine,2,3-divinylpiperazine, 1,4-divinylpiperazine, 2,5-divinylpiperazine,2,6-divinylpiperazine, 2,2-divinylmorpholine, 2,3-divinylmorpholine,3,3-divinylmorpholine, 2,4-divinylmorpholine, 3,4-divinylmorpholine,2,5-divinylmorpholine, 3,5-divinylmorpholine, 2,6-divinylmorpholine,etc., as well as allyl-vinyl and diallyl analogs of these),cyclohexa-1,4-diene-1-carboxylic acid, cyclohexa-2,5-diene-1-carboxylicacid, diallyl ether, muurolenes, germacradienes, germacradienols,curcumin, demethoxycurcumin, bisdemethoxycurcumin, velleral, valencene,capsidiol, bisabolols, aristolochene, amorpha-4,11-diene, eremophilene,gurjurene, bergamotenes, lavandulol, himachalenes, amorphenes,safranates, safranal, perillaldeyhde, perillalcohol, carveol, carvones,elemol, jasmolone, nootkatone, tagetone, solanone, vetivones, santalols,lindestrene, abietic acid, artemisinic acid, caryophyllenes, cadinenes,guaienes, irones, selinenes, damascones, ionones, isolimonene,dipentene, terpinenes, phellandrenes, linalool, nerol, piperine,chavicine, farnesol, myrcene, ocimene, damascenones, gurjurenes,eremophilene, curzerenone, pyrethrolone, vetivones, sesquiphellandrenes,cadinenes, zingiberene, parthenin, santonin, geraniol, limonene,bisabolenes, citral, jasmone, cannabidiol, valerenic acid, nerolidol,geranic acids, etc. Substituted analogs (e.g., the alkyl, (hetero)aryl,(hetero)cyclic, allyl, and/or vinyl moiety having 1, 2, or 3substituents) and/or protected analogs (e.g., in amide, carbamate,ester, ether, alkyl, silyl, etc., form) of any of these, as relevant,are also within the scope of the invention.

Suitable oxidizing agents to produce bisepoxides useful in the inventivemethod include any of those known to persons of ordinary skill in theart, such as various peroxides, e.g., hydrogen peroxide, peracetic acid,OXONE®, m-chloroperbenzoic acid (MCPBA), and tert-butyl hydroperoxide.These and any further suitable epoxidizing agent known to those ofordinary skill in the art can be used to produce a bisepoxide within thescope of the invention, i.e., an organic compound having at least two,and preferably only two, epoxide moieties.

A nucleophile useful for the present invention is any one capable offorming a ring upon reaction with two epoxides upon a single molecule.The nucleophile preferably comprises a heteroatom, particularly N, O, S,or P, and the heteroatom preferably works as the nucleophilic element.The nucleophile is preferably an amine (including ammonia), a phosphine(including PH₃), hydrogen sulfide, HS⁻, HO⁻, or water. Preferrednucleophiles include ammonia, primary amines, amino acids, alkylamines(e.g., methylamine, ethylamine, isopropylamine, propylamine, etc.),arylamines (e.g., aniline), and arylalkylamines (e.g., benzylamine,racemic, R, or S-analogs of α-alkylbenzylamines, etc.) including asaturated or unsaturated, bicyclic or tricyclic fused hydrocarbon groupwhich may be substituted, or a saturated or unsaturated, bicyclic, ortricyclic fused heterocyclic group which may be substituted.Particularly preferred nucleophiles include ammonia, methylamine,ethylamine, optionally substituted benzylamine, optionally substituted2-phenylethylamine, optionally substituted 1-phenylethylamine (racemic,R, or S), optionally substituted aniline, hydrazine, and1,2-ethylenediamine. Any nucleophile having two or more reactivemoieties may be protected. Most preferred nucleophiles are presentlyconsidered to be ammonia or benzylamine. Isotopically enrichednucleophiles, and/or bisepoxides, are also contemplated, e.g., thosecomprising enriched isotopes, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ³²P,and/or ³³P.

A heteropolycycle within the scope of the invention may contain 2, 3, 4,or 5 rings, more preferably being bicyclic, tricyclic, or tetracyclic,most preferably being bicyclic. Within the meaning of the invention, aheteroatom is not a carbon atom and not a hydrogen atom, and ispreferably an atom having at least two covalent bonding sites, morepreferably O, N, S, P, and/or Se, most preferably N and/or O. Moreover,a heteropolycycle according to the invention preferably contains two ormore heteroatoms interrupting the carbon backbone of the ring(s),including nitrogen, oxygen, sulfur, and/or phosphorus, more preferably2, 3, 4, or 5 of such heteroatoms, most preferably 2 or 3 suchheteroatoms, particularly preferably 2 heteroatoms. Each heteroatom inthe heteropolycycle may be nitrogen, or each heteroatom in theheteropolycycle may be oxygen, or the heteroatoms may be a mixture ofnitrogen, sulfur, phosphorus, and/or oxygen, or the heteroatoms may be amixture of nitrogen and oxygen. The heteropolycycle preferably has atleast one (e.g., 1, 2, or 3) heteroatom capable of bonding to three ormore atoms and preferably contains at least one nitrogen and/or oxygen,most preferably one or two nitrogens or only two nitrogens. Theheteroatoms are preferably distributed in any of the contiguous rings ofthe polycyclic backbone, though more preferable embodiments contain allheteroatoms in the backbone of the main (or larger) ring of thepolycycle.

Heteropolycycle products within the scope of the inventive methodinclude any diazabicycle, oxazabicycle, azaphosphobicycle,oxaphosphobicycle, diazatricycle, oxazatricycle, azaphosphotricycle,oxaphosphotricycle, optionally substituted and/or fused with aliphaticor aromatic rings, insofar as the heteropolycycle contains at least twoheteroatoms (e.g., N, O, S, P, and/or Se) within the backbone of thepolycycle and the polycycle is at least bicyclic. Heteropolycyclesobtained according to aspects of the invention preferably include one ormore optionally substituted analogs of 2,5-diazabicyclo[2.2.2]octane,3,8-diazabicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.1]heptane,3,6-diazabicyclo[3.1.1]heptane, 3,6-diazabicyclo[3.1.0]hexane,2,5-diazabicyclo[2.2.0]hexane, 2-aza-5-oxabicyclo[2.2.2]octane,3-aza-8-oxabicyclo[3.2.1]octane, 2-aza-5-oxabicyclo[2.2.1]heptane,3-aza-6-oxabicyclo[3.1.1]heptane, 3-aza-6-oxabicyclo[3.1.0]hexane,2-aza-5-oxabicyclo[2.2.0]hexane, 2-aza-5-phosphabicyclo[2.2.0]hexane,3-aza-6-phosphabicyclo[3.1.0]hexane,6-aza-3-phosphabicyclo[3.1.0]hexane,2-aza-5-phosphabicyclo[2.2.1]heptanes,2-aza-5-phosphabicyclo[2.2.2]octane,6-aza-3-phosphabicyclo[3.1.1]heptanes,3-aza-6-phosphabicyclo[3.1.1]heptanes,3-aza-8-phosphabicyclo[3.2.1]octane,8-aza-3-phosphabicyclo[3.2.1]octane,3-oxa-6-phosphabicyclo[3.1.0]hexane,6-oxa-3-phosphabicyclo[3.1.0]hexane,2-oxa-5-phosphabicyclo[2.2.0]hexane,2-oxa-5-phosphabicyclo[2.2.1]heptanes,2-oxa-5-phosphabicyclo[2.2.2]octane,6-oxa-3-phosphabicyclo[3.1.1]heptanes,3-oxa-6-phosphabicyclo[3.1.1]heptanes,3-oxa-8-phosphabicyclo[3.2.1]octane,8-oxa-3-phosphabicyclo[3.2.1]octane, etc.

A person of ordinary skill in the art will immediately recognize thatthe aliphatic carbons of the heteropolycycles, and, correspondingly,their precursors, may be substituted with a substituent includingmethyl, ethyl, C₃, C₄, C₅, or C₆ alkyl groups, ethers comprising 1, 2,3, 4, 5, or 6 carbons, alkylhalides comprising 1, 2, 3, 4, 5, or 6carbons, primary, secondary, and/or tertiary amines comprising 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 carbons, ammonium groups comprising 1, 2, 3, 4,5, 6, 7, 8, 9, or 10 carbons, halides (fluoride, chloride, bromide,and/or iodide), nitriles, isonitriles, azides, cyanates, isocyanates,thiocyanates, isothiocyanates, nitros, nitrosyls, oximes, hydroxyls,alkyl ethers, thiols, thioethers, aryls, aryl ethers, sulfonates,acyloxy groups (optionally reversed) comprising 1, 2, 3, 4, 5, or 6carbons, keto or aldehyde groups comprising 1, 2, 3, 4, 5, or 6 carbons,primary and/or secondary (optionally reversed) amide or sulfonamidegroups comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 carbons, carbamategroups comprising 1, 2, 3, 4, 5, or 6 carbons. Suitable substituents aredescribed in WO 2000/035915 A1 at pg. 7, l. 20, to pg. 8, l. 24, pg. 9,l. 5, to pg. 10, l. 35, esp. substituents upon phenyl groups and otherrings (the entire disclosure of WO 2000/035915 A1 is incorporated hereinby reference). US 2005/0020645 A1, also incorporated in its entiretyherein by reference, discloses suitable substituents, for example, at¶¶[0014], [0038], [0043], [0046], [0051], [0053], [0055], [0057], and[0059]. Certain embodiments exclude hydroxyl and or ether substituents.Particularly preferred substituents are methyl, ethyl, methoxy,carboxylate, or fluoro. Here it should be noted that “nature loves amethyl group.” Indeed, preferred substituents include methyl groups,particularly those which would impart stereochemistry, i.e., chirality,upon the heteropolycycle, or enhance the stereochemical effect, orsimply offend the symmetrically minded's sense of natural order.

An aspect of the invention provides a reaction mixture obtained by theabove method, the separation of which into pure components is routine tothose of ordinary skill in the art, e.g., by chromatography or relatedpreferential adhesion, adsorption, and/or seclusion techniques, bydistillation, by separative crystallization, by sublimation, etc.

A preferred route in certain embodiments of the invention may employ theso-called “Rabony's reagent.” Rabony's reagent is not to be confusedwith the otherwise well-known Gerkin's reagent (likewise, a spontaneousand potent reagent). Rabony's reagent essentially comprises aconcentrated or partially concentrated hydrobromic acid solution inacetic acid. Reacting a diol within the scope of the invention withRabony's reagent has been surprisingly shown to produce a diacetate ofthe diol. While the diacetate is not an exceptionally good leavinggroup, the facility and atom efficiency of the Rabonyan approachprovides readily apparent advantages to those of ordinary skill in theart. A useful modification of Rabony's reagent could be concentrated HBrin trifluoroacetic acid or methanesulfonic acid.

After affixing a leaving group to the diol, or converting the diol intoa leaving group, preferably using methanesulfonyl chloride to obtain amesylate, a final ring closure may be performed with any at most primaryamine known in the art, including ammonia, primary amines, and diamines,including optionally substituted alkylamines, arylamines,alkylarylamines (esp. benzylamines), etc. For example, ammonia,methylamine, ethylamine, benzylamine, isopropylamine, or the like, maybe used. Asymmetric amines are specifically contemplated for use withinthe scope of the invention. That is, any of (R) or (S)1-phenylethylamine, (R) and (S) 1-(3-methoxyphenyl)-ethylamine, (R) or(S) 1-phenylbutylamine, (R) or (S) 2-hexylamine, (R) or (S)2-heptylamine, (R) or (S) 2-octylamine, (R) or (S)1-(2-naphthyl)ethylamine, (R) or (S) 3-methyl-2-butylamine, (R) or (S)1-indanamine, (R,R) or (S,S)-trans-2-benzyloxy-cyclopentylamine, (R) or(S) 3,3-dimethyl-2-butylamine, and/or (R) or (S)N-methyl-1-phenylpropan-2-amine may be used, whereby a diastereomericoutcome is immediately produced upon reaction with certain racemicdiazabicyclics.

The method of synthesizing the pharmaceutical compound is preferablyone, wherein the pharmaceutical compound is a ziprasidone, ranolazine,olanzapine, eszopiclone, linezolid, quetiapine, imatinib, ciprofloxacin,levofloxacin, aripiprazole, sildenafil, vardenafil, donepezil,levocetirizine, gatifloxacin, buspirone, trazodone, doxazosin,terazosin, itraconazole, terconazole, timolol, meclizine, mirtazapine,sunitinib, raloxifene, levosalbutamol (levalbuterol), bupropion, orropinirole analog. That is, an aspect of the invention comprisessubstituting the piperazine (or amine) core of any one of these or otherpharmaceutically active compounds.

The pharmaceutical compound may be preferably in the form of a salt incertain embodiments of the invention. Pharmaceutically acceptable acidaddition salts of the pharmaceutical compound (and/or theheteropolycycle) preferably employ an acid used to prepare thepharmaceutically acceptable acid addition salts of heteropolycycleand/or pharmaceutical compounds of the invention are those which formnon-toxic acid addition salts, i.e., salts containing pharmacologicallyacceptable anions, such as the hydrochloride, hydrobromide, hydroiodide,nitrate, sulfate, bisulfate, phosphate, acetate, lactate, citrate,malonate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate,saccharate, benzoate, methanesulfonate, ethanesulfonate,benzenesulfonate, p-toluenesulfonate, pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)], formate, arginine,aspartic acid, and glutamic acid salts.

In embodiments of the invention, the further processing in the method ofsynthesizing the heteropolycycle and/or pharmaceutical agent preferablycomprises contacting at least one hydroxyl group of the diol compoundwith a leaving group forming compound, thereby converting the hydroxylgroup into a better leaving group relative to the hydroxyl group, toobtain an intermediate comprising a leaving group-activated hydroxylgroup. In certain embodiments the contacting preferably comprisescontacting two hydroxyl groups of the diol compound with the leavinggroup forming compound, to obtain the intermediate comprising twoleaving-group activated hydroxyl groups. Certain embodiments preferablyconvert two or all of the free hydroxyl groups into leaving groupsdescribed above. Using Rabony's reagent, i.e., HBr in acetic acid,preferably 33 wt. %, a surprising conversion of the hydroxyl groups intoacetates can be achieved, and these acetates can serve as leavinggroups. The Rabonyan route may preferably use HBr in trifluoroaceticacid or trifluoromethanesulfonic acid, preferably concentrated,preferably at least 20, 25, 30, or even 33 wt. %. Rabony's reagent oraqueous HBr may be preferred in certain embodiments to convert hydroxylgroups on an, e.g., pyrrolidine, piperidine, and/or azepane ring, to,e.g., triflates. A bis-triflate, or any leaving group activated species,may be converted to a bicyclic compound in the presence of an iodidesalt, e.g., KI, to improve its utility as a leaving group.

The method of producing a heteropolycycle and/or pharmaceutical compoundmay preferably further comprise protecting a nitrogen of theheteropolycycle with a protecting group. Protecting groups within thescope of the invention include, for example, as carbamates (e.g.,methyl, ethyl, 9-fluorenylmethyl, 2-chloroethyl, 2,2,2-trichloroethyl,tert-butyl, vinyl, allyl, benzyl and substituted derivatives thereofsuch as 4-methoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl, diphenylmethyl,triphenylmethyl, etc.), as amides (e.g., acetyl, chloroacetyl,trichloroacetyl, trifluoroacetyl, phenylacetyl, benzoyl, pivaloyl,etc.), N-alkyl derivatives (e.g., N-methyl, N-ethyl, N-cycloalkyl,N-tert-butyl, N-allyl, N-benzyl, N-(methoxybenzyl), N-(dimethoxybenzyl),N-(trimethoxybenzyl), N-diphenylmethyl, N-triphenylmethyl, etc.), andother miscellaneous protecting groups, e.g., phthaloyl, N-silyl,N-sulfenyl, N-sulfonyl, N-tosyl (i.e., N-p-toluenesulfonyl), orN-methanesulfonyl protecting groups. Appropriate protecting groups, asdescribed herein, for respective heteroatoms and functional groups inany starting material, bisepoxide, diol, heteropolycycle, or otherspecies described herein, can be selected from Greene's ProtectiveGroups in Organic Synthesis, 4^(th) ed. (ISBN-10: 0471697540) or 5^(th)ed. (ISBN-10: 1118057481), each of which is incorporated herein in itsentirety.

The method of producing a heteropolycycle and/or pharmaceutical compoundmay preferably further comprise racemizing hydroxyl groups of the diolcompound, to obtain a stereochemically altered diol compound.Particularly, the racemization may involve an epimerization with an insitu Meerwein-Ponndorf-Verley reduction coupled with an Oppenaueroxidation, using, e.g., aluminum isopropoxide and isopropanol withacetone. Such an epimerization, particularly in the case of6-hydroxymethyl-3-hydroxypiperidine, may racemize the diastereomersunder mild conditions, and should ultimately lead to desireddiastereomers, which are bis-equatorial. Another type ofstereoequilibrating the cyclic aminodiol intermediate mixtures had fromreacting the bisepoxides with nucleophiles consists of allowing furtherprocessing under conditions that favor substitution by an S_(N)1mechanism, most preferably to enrich the desired intermediatediastereomer apt for bicyclization by conducting bicyclization underS_(N)1-favoring conditions, e.g., by employing a polar protic reactionsolvent, e.g., an alcohol, organic acid, water, etc., instead of anon-polar solvent, e.g., toluene, pet ether, cyclohexane, etc., or apolar aprotic solvent, e.g., DMSO, NMP, THF, etc.

The method of producing a heteropolycycle and/or pharmaceutical compoundmay preferably further comprise contacting the diol compound withthionyl chloride, or by optionally heating the diol compound in thepresence of a mineral acid, such as H₂SO₄, HCl, HBr, H₃PO₄, andpolyphosphoric acid, or acetic acid, or catalytic p-toluenesulfonic acidwith heating, preferably in a Dean-Stark trap, or optionally heating inthe presence of tosyl chloride and/or mesyl chloride in an inertsolvent, such as CH₂Cl₂, in the presence of an inert base, such aspyridine or triethylamine. The method in such embodiments may produce,for example a heteropolycycle comprising a2-aza-5-oxabicyclo[2.2.2]octane, a 3-aza-8-oxabicyclo[3.2.1]octane, a2-aza-5-oxabicyclo[2.2.1]heptane, a 3-aza-6-oxabicyclo[3.1.1]heptane, a3-aza-6-oxabicyclo[3.1.0]hexane, a 2-aza-5-oxabicyclo[2.2.0]hexane, ormixtures of two of these, any of which are optionally substituted.

Certain embodiments of the invention will produce a heteropolycycle ofthe formula:

or a pharmaceutically acceptable salt thereof, wherein X is NZ, O, PZ,or S; m is 0, 1, 2, 3, or 4; n is 0, 1, 2, 3 or 4; o is 0, 1, 2, 3, or4; m, n, and 0 cannot all be 0 and if m and/or o are not 0, then n mustbe 0; Z is independently H, a C₁, C₂, C₃, C₄, or C₅ alkyl group (such asmethyl, ethyl, isopropyl, propyl, sec-propyl, butyl, isobutyl,sec-butyl, tert-butyl, phenyl, benzyl, p-methoxybenzyl,3,4-dimethoxybenzyl, p-methoxyphenyl, etc.), a carbamate (such as a BOCgroup, Cbz group, Moz group, etc.), a MOM group, an acyl group (such asan acetyl group, a benzoyl group, pivaloyl group, a trifluoroacetylgroup, etc.), a sulfonamide (such as a mesyl group, a besyl group, atosyl group, etc.), or an FMOC group.

The 1,5-Hexadiene Route to (±) 2,5-Diazabicyclo[2.2.2]octane

1:2,5:6-Bisepoxyhexane was reacted with a slight excess of benzylaminein hot methanol, either in an autoclave or under reflux for 4 to 24hours. Under both conditions, excellent yields (˜90-95%) of1-benzyl-6-(hydroxymethyl)-piperidin-3-ol and 1-benzylazepane-3,6-diol(both as mixtures of diastereomers) were obtained via kugelrohrdistillation of the crude reaction mixture. The diastereomers of1-benzyl-6-(hydroxymethyl)piperidin-3-ol and 1-benzylazepane-3,6-diolwere then treated with an excess of mesyl chloride in dichloromethane inthe presence of excess trimethylamine at ice-salt bath temperatures.Allowing for expected longer reaction times for mesylation of secondaryalcohols, the mixtures were stirred for at least 48 hrs at roomtemperature. Then, by careful quenching with aq. KHCO₃ in the cold topH=8 and extraction with dichloromethane, followed by chromatography onsilica gel, gave moderate to good yields (˜62-67%) of the correspondingdimesylates as mixtures of diastereomers. These mixtures, dimesylated1-benzyl-6-(hydroxymethyl)piperidin-3-ol and 1-benzylazepane-3,6-diol,were then used for the ultimate bicyclization. The mesylated1-benzyl-6-(hydroxymethyl)-piperidin-3-ol and 1-benzylazepane-3,6-diolwere reacted with excess ammonia in methanol in a steel autoclave for24-48 hrs. Evaporation and chromatography on silica gel afforded purediazabicycles, 2,5-diazabicyclo[2.2.2]octane(s) and3,8-diazabicyclo[3.2.1]octane.

The 1,4-Pentadiene Route to (±) 2,5-Diazabicyclo[2.2.1]heptane and3,6-Diazabicyclo[3.1.1]heptanes (Prophetic)

1:2,4:5-Bisepoxypentane can be reacted with roughly one equivalent of,e.g., ammonia or benzylamine in an inert solvent at room temperature upto the boiling point of the solvent, or in an autoclave, for 5 to 60 hr,preferably at least 24 hr, preferably at least 36 hr, to yield apiperidin-3,5-diol as a mixture of diastereomers. Purification can becarried out by standard techniques, such as chromatography, kugelrohrdistillation, or short-path distillation. The piperidin-3,5-diol and2-hydroxymethyl-pyrrolidin-4-ol diastereomers can be treated with, e.g.,mesyl chloride in, e.g., dichloromethane in the presence of an inertbase under cooling. The mesylated piperidin-3,5-diol and2-hydroxymethyl-pyrrolidin-4-ol can be reacted with, e.g., ammonia or analkyl or benzyl amine, in an inert solvent in a steel autoclave for24-48 hrs. Evaporation and chromatography should afford2,5-diazabicycl[2.2.1]heptane(s) and mainly3,6-diazabicyclo[3.1.1]heptane, which can be optionally further reacted,e.g., to incorporate it into a pharmaceutical precursor.

The 1,3-Butadiene Route to 3,6-Diazabicyclo[3.1.0]hexane (Prophetic)

1:2,3:4-Bisepoxybutane can be reacted with, e.g., ammonia or benzylaminein an inert solvent at room temperature up to the boiling point of thesolvent, or in an autoclave, for 15 min to 1 hr, to yield apyrrolidin-3,4-diol as a mixture of diastereomers. Purification can becarried out by standard techniques. The pyrrolidin-3,4-dioldiastereomers can be treated with a leaving group forming compound in aninert solvent in the presence of an inert base under cooling. Themesylated pyrrolidin-3,4-diol can be reacted with, e.g., ammonia, analkyl amine, benzylamine, etc., in an inert solvent in a steel autoclavefor 24-48 hrs. Evaporation and chromatography should afford3,6-diazabicyclo[3.1.0]hexane.

The 1,5-Hexadiene Route to 5-Benzyl-2-oxa-5-azabicyclo[2.2.2]octane and3-Benzyl-8-oxa-3-azabicyclo[3.2.1]octane (Prophetic)

To obtain an oxygen-bridged heteropolycycle, a cyclic aminodiol can bedehydrated by known methods to obtain an ether-linkage from two hydroxylfunctions, such as the diols in the case of the 1,5-hexadiene synthesis.For example, compounds had from reacting benzylamine as nucleophile withhexadiene-1,5-bisepoxide, a mixture of1-benzyl-6-(hydroxymethyl)piperidin-3-ol and 1-benzylazepane-3,6-diol,can be reacted with 1-5 eq. of thionyl chloride in DMF at roomtemperature, heating to reflux, allowed to cool back to roomtemperature, then evaporated to dryness and purified via chromatographyto obtain 5-benzyl-2-oxa-5-azabicyclo[2.2.2]octane and3-benzyl-8-oxa-3-azabicyclo[3.2.1]octane. See Revesz. L.; Blum, E.;Wicki, R. Synthesis of novel piperazine based building blocks:3,7,9-triazabicyclo[3.3.1]nonane, 3,6,8-triazabicyclo[3.2.2]nonane,3-oxa-7,9-diazabicyclo[3.3.1]nonane and3-oxa-6,8-diazabicyclo[3.2.2]nonane. Tetrahedron Lett. 2005, 46(33),5577-5580, which is incorporated herein in its entirety. Similarly, thedehydrative cyclization may be carried out under the action of, e.g.,p-toluenesulfonic acid, hydrohalide acids, polyphosphoric acid, and/orsulfuric acid, under the dehydrating action of mol sieves or othermethods of ether formation from two alcohol functional groups known tothose skilled in the art. Alternatively, the bisepoxide can be reactedwith an equivalent of, e.g., optionally deprotonated water or hydrogensulfide, e.g., in THF, optionally again deprotonated, e.g., with NaH, toobtain a diol compound. The diol compound may be handled in any mannerdescribed above to form a heteropolycycle.

1: A mixture of heteropolycycles, the mixture comprising:

or salt(s) thereof, any of which heteropolycycles are optionallysubstituted on ring carbons, wherein A is N—R, P—R, O, or S, X is N—R′,P—R′, O, or S, R, when present, is a protecting group, H, benzyl,methyl, ethyl, C3-alkyl, C4-alkyl, or a protecting group, and R′, whenpresent, is independently a protecting group, H, benzyl, methyl, ethyl,C3-alkyl, C4-alkyl, or a protecting group. 2: The mixture of claim 1,comprising

which are optionally substituted, and/or salt(s) thereof. 3: The mixtureof claim 1, comprising: a 2,5-diazabicyclo[2.2.2]octane and a3,8-diazabicyclo[3.2.1]octane; or a 2-aza-5-oxabicyclo[2.2.2]octane anda 3-aza-8-oxabicyclo[3.2.1]octane, which are optionally substituted,and/or salt(s) thereof. 4: The mixture of claim 3, comprising at least75 wt. % the 2,5-diazabicyclo[2.2.2]octane, and/or a salt thereof. 5:The mixture of claim 4, wherein R is benzyl. 6: The mixture of claim 4,wherein R is methyl. 7: The mixture of claim 3, comprising at least 75wt. % the 3,8-diazabicyclo[3.2.1]octane, and/or a salt thereof. 8: Themixture of claim 7, wherein R is benzyl. 9: The mixture of claim 7,wherein R is methyl. 10: The mixture of claim 3, comprising at least 75wt. % the 2-aza-5-oxabicyclo[2.2.2]octane, and/or a salt thereof. 11:The mixture of claim 3, comprising at least 75 wt. % the3-aza-8-oxabicyclo[3.2.1]octane, and/or a salt thereof. 12: The mixtureof claim 1, comprising

which are optionally substituted, and/or salt(s) thereof. 13: Themixture of claim 1, comprising: a 2,5-diazabicyclo[2.2.1]heptane and a3,6-diazabicyclo[3.1.1]heptane; or a 2-aza-5-oxabicyclo[2.2.1]heptaneand a 3-aza-6-oxabicyclo[3.1.1]heptane, which are optionallysubstituted, and/or salt(s) thereof. 14: The mixture of claim 13,comprising at least 75 wt. % the 2,5-diazabicyclo[2.2.1]heptane, and/ora salt thereof. 15: The mixture of claim 14, wherein R is benzyl. 16:The mixture of claim 14, wherein R is methyl. 17: The mixture of claim13, comprising at least 75 wt. % the 3,6-diazabicyclo[3.1.1]heptane,and/or a salt thereof. 18: The mixture of claim 17, wherein R is benzylor methyl. 19: The mixture of claim 13, comprising at least 75 wt. % the2-aza-5-oxabicyclo[2.2.1]heptane, and/or a salt thereof. 20: The mixtureof claim 13, comprising at least 75 wt. % the3-aza-6-oxabicyclo[3.1.1]heptane, and/or a salt thereof.